The present invention is generally directed to an improved synthetic process for the preparation of β-lactams.
β-lactams have utility in a variety of applications. They possess biological activity and are used, as such, for certain applications. They also serve as synthetic intermediates for a variety of other biologically active compounds.
In Chem. Rev. 1989, 89, 1447-1465, Hart et al. describe the use of enolate-imine condensation reactions to prepare, β-lactams. These routes include the use of zinc enolates and Reformatsky reagents as well as reaction of metal and boron enolates with unsaturated nitrogen-containing compounds. In particular, Hart et al. disclose the reaction of N(trimethylsilyl)imines with a lithium enolate of ethyl butyrate to produce a N-unsubstituted-3-ethyl-4-propyl-azetidin-2-one. Generally, due to the decomposition of the intermediates, the reactions require temperature conditions of −78° C.
In U.S. Pat. No. 5,723,634, Holton et al. describe a synthetic pathway for the preparation of N-unsubstituted- and N-substituted-3-hydroxy β-lactams. A lithium enolate (prepared from ethyl triethylsiloxyacetate and lithium diisopropyl amide) cyclocondenses with an imine (prepared from an aryl aldehyde and lithium hexamethyldisilazide) to produce a 3-triethylsiloxy-4-arylazetidin-2-one. The resulting arylazetidin-2-one can be converted to a N-benzoyl β-lactam by treatment with benzoyl chloride in the presence of a base.